Gluconeogenesis is necessary during starvation, and between meals. Regulation become aberrant under certain conditions such as diabetes mellitus. Gluconeogenesis has been most studied in rats; pathways and regulation projected mainly on these data. Recent studies with various species suggest that rats may not be a proper model for gluconeogenesis in humans due to differences in the cellular location of phosphoenolpyruvate (PEP) carboxykinase and in the redox state of rat mitochondria vs those from humans and other species during conditions conducive to gluconeogenesis. Dietary factors such as fatty acids which accelerate gluconeogenesis in rats inhibit this process in species metabolically more like humans. Observations on gluconeogenesis and its regulation will be made and results compared to those from rats and other species. We use the fasted rabbit as its distribution of hepatic PEP carboxykinase is somewhat like that of guinea pigs and humans. We find cytosolic carboxykinase activity to be enhanced by starvation, diabetes, hydrocortisone and mannoheptulose. We find that the rate of conversion of lactate or dihydroxyacetone to glucose by livers from fasted rabbits is enhanced 1.7 fold by glucagon, epinephrine, and cyclic AMP. We will investigate the mode of action of epinphrine and glucagon with alpha- and beta-adrenergic agonists and antagonists. The influence of adrenalglucocorticoid deficiency on gluconeogenesis is isolated rabbit livers will be investigated both in the presence and absence of effectors such as glucagon and epinephrine. A regulatory role for L-tryptophan (or derivative thereof) in normal carbohydrate metabolism in various species will be sought as this effector is unable to influence gluconeogenesis in diabetic rats; attempts will be made to explain theis ineffectiveness. We will study the effectiveness of quinolinate as an inhibitor in carboxykinase preps from hepatic, renal and adipose tissues of normal and diabetic rats.